Neuropharmacology
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Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). ⋯ In primary neurons, l-CDL indirectly reduced an increase in CXCR2 by astrocyte-conditioned medium but did not act directly on the CXCR2 site. Taken together, our data first demonstrate that an NFκB-dependent CXCL1/CXCR2 signaling pathway is involved in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely attenuates this inflammation through down-regulation of this signaling pathway.
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Deaths from opioid use are increasing in the US, with a growing proportion due to synthetic opioids. Until 2013, sporadic outbreaks of fentanyl and fentanyl analogs contaminating the heroin supply caused some deaths in heroin users. Since then, fentanyl has caused deaths in every state and fentanyl and its analogs have completely infiltrated the North American heroin supply. ⋯ Due to their high affinity for μ-opioid receptors, larger doses of naloxone are required to reverse the effects than are commonly used. Synthetic opioids are an increasingly major public health threat requiring vigilance from multiple fields including law enforcement, government agencies, clinical chemists, pharmacists, and physicians, to name a few, in order to stem its tide. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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Diversion of synthetic cannabinoids from the lab to drugs of abuse has become increasingly prevalent in recent years. Moreover, as earlier synthetic cannabinoids were banned, manufacturers introduced a new supply of novel compounds to serve as replacements. Hence, the chemical diversity of synthetic cannabinoid analogs has also rapidly increased. ⋯ S., MAM-2201, EAM-2201, JWH-210, AM-2233, and AM-1220. These results indicate that the evolution of the synthetic cannabinoid drug market may be focused toward compounds with increased potency. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
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The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV1.7 subtype of voltage-gated sodium (NaV) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms. ⋯ HwTx-IV was also approximatively 850 times more efficient to inhibit TTX-sensitive than TTX-resistant sodium currents recorded from mouse dorsal root ganglia neurons. Finally, based on our data, we predict that blockade of the NaV1.6 channel subtype was involved in the in vivo toxicity of HwTx-IV, although this toxicity was more than 2 times lower than that of TTX. In conclusion, our results provide detailed information regarding the effects of HwTx-IV and allow a better understanding of the side-effect mechanisms involved in vivo and of channel subtype interactions resulting from the toxin activity.
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A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. ⋯ This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues.